Atypical haemolytic–uraemic syndrome (aHUS) is characterized by endothelial damage leading to renal failure. aHUS has a proven genetic background... To date, underlying genetic factors have been identified in complement components and complement regulators among ∼50% of aHUS patients... Following yet not well-identified triggering events, endothelial cells lose their integrity and become a target for an uncontrolled complement attack... The release of C5a and the inactive form—in terms of cytolytic effect—of the membrane attack complex (MAC) C5b-9 induces a procoagulant phenotype... Despite the fact that plasma exchanges are the treatment of choice in severe thrombotic thrombocytopaenic purpura, their efficacy in aHUS is not guaranteed... Therefore, other therapeutic procedures, in particular complement-blocking agents, may be of benefit, and considering the severity of this condition are fully justified... To this day, >50 cases of patients who received eculizumab for aHUS have been published or included in an international multicentre prospective Phase II trial... Kim et al. and Garjou et al., in two articles that appear in this issue of the Clinical Kidney Journal, describe the outcome of aHUS in two additional cases of patients who received eculizumab for this syndrome occurring in their native kidneys... It comes as no surprise that plasma exchanges were not beneficial in the patient with MCP mutation... MCP is classically associated with a childhood onset, a spontaneous abortion of the TMA and recurrent episodes... After failure of plasma exchanges, eculizumab induced an increase in platelet counts and haemolysis was stopped... The patient with MCP mutation who was treated later than 3 months after the onset did not recover his kidney function... In these cases, the tolerability was good... It appears that eculizumab, the first targeted terminal complement inhibitor, is able to provide an effective and generally well-tolerated treatment for patients suffering from aHUS.

fig1: The complement system is a major innate immune defence mechanism. Complement may be activated by the classical, lectin or alternative pathways, all leading to the cleavage of the inactive central component C3 to biologically active C3b. C3b binds covalently to any surface, either foreign or self. When C3b is bound to positively charged surfaces (called alternative pathway activator surfaces as present in microorganisms) C3b interacts with factor B (FB) to form the C3 convertase (C3bBb) of the alternative pathway amplification loop and may generate a C5 convertase leading to the release of C5a, which is also an anaphylatoxin, and C5b which initiates the formation of the membrane attack complex (MAC), by binding C6 and C7. The C5b67 inserts into the membrane where it binds C8 and many molecules of C9, forming a pore. It can be cytolytic, forming a transmembrane channel, which causes osmotic lysis of the target cell or sublytic, associated with cell activation. In order to avoid complement hyperactivation, the alternative pathway C3 convertase is tightly regulated.

Mentions:
Atypical haemolytic–uraemic syndrome (aHUS) is characterized by endothelial damage leading to renal failure. aHUS has a proven genetic background [1]. To date, underlying genetic factors have been identified in complement components and complement regulators among ∼50% of aHUS patients [2, 3]. The disease-associated genes include C3 and factor B, which form the complement amplification convertase C3bBb and the regulators factor H (CFH, a plasma gycoprotein), membrane cofactor protein (CD46, MCP) and factor I (a plasma serine protease) which concur to controlling C3 convertase activity (Figure 1). In addition, autoantibodies recognizing factor H have been identified as being associated with haemolytic–uraemic syndrome (HUS) [4]. Over the last decade, a clear link has been demonstrated between this disorder and a defective regulation of the complement system components [5]. Thus, it is generally accepted that aHUS is a disease of excessive complement activation in the kidney glomerular and arteriolar cells. Following yet not well-identified triggering events, endothelial cells lose their integrity and become a target for an uncontrolled complement attack. The release of C5a and the inactive form—in terms of cytolytic effect—of the membrane attack complex (MAC) C5b-9 induces a procoagulant phenotype. This deleterious triggering of the complement and the coagulation cascades leads to the development of the thrombotic microangiopathy (TMA) that characterizes aHUS [6].

fig1: The complement system is a major innate immune defence mechanism. Complement may be activated by the classical, lectin or alternative pathways, all leading to the cleavage of the inactive central component C3 to biologically active C3b. C3b binds covalently to any surface, either foreign or self. When C3b is bound to positively charged surfaces (called alternative pathway activator surfaces as present in microorganisms) C3b interacts with factor B (FB) to form the C3 convertase (C3bBb) of the alternative pathway amplification loop and may generate a C5 convertase leading to the release of C5a, which is also an anaphylatoxin, and C5b which initiates the formation of the membrane attack complex (MAC), by binding C6 and C7. The C5b67 inserts into the membrane where it binds C8 and many molecules of C9, forming a pore. It can be cytolytic, forming a transmembrane channel, which causes osmotic lysis of the target cell or sublytic, associated with cell activation. In order to avoid complement hyperactivation, the alternative pathway C3 convertase is tightly regulated.

Mentions:
Atypical haemolytic–uraemic syndrome (aHUS) is characterized by endothelial damage leading to renal failure. aHUS has a proven genetic background [1]. To date, underlying genetic factors have been identified in complement components and complement regulators among ∼50% of aHUS patients [2, 3]. The disease-associated genes include C3 and factor B, which form the complement amplification convertase C3bBb and the regulators factor H (CFH, a plasma gycoprotein), membrane cofactor protein (CD46, MCP) and factor I (a plasma serine protease) which concur to controlling C3 convertase activity (Figure 1). In addition, autoantibodies recognizing factor H have been identified as being associated with haemolytic–uraemic syndrome (HUS) [4]. Over the last decade, a clear link has been demonstrated between this disorder and a defective regulation of the complement system components [5]. Thus, it is generally accepted that aHUS is a disease of excessive complement activation in the kidney glomerular and arteriolar cells. Following yet not well-identified triggering events, endothelial cells lose their integrity and become a target for an uncontrolled complement attack. The release of C5a and the inactive form—in terms of cytolytic effect—of the membrane attack complex (MAC) C5b-9 induces a procoagulant phenotype. This deleterious triggering of the complement and the coagulation cascades leads to the development of the thrombotic microangiopathy (TMA) that characterizes aHUS [6].

Atypical haemolytic–uraemic syndrome (aHUS) is characterized by endothelial damage leading to renal failure. aHUS has a proven genetic background... To date, underlying genetic factors have been identified in complement components and complement regulators among ∼50% of aHUS patients... Following yet not well-identified triggering events, endothelial cells lose their integrity and become a target for an uncontrolled complement attack... The release of C5a and the inactive form—in terms of cytolytic effect—of the membrane attack complex (MAC) C5b-9 induces a procoagulant phenotype... Despite the fact that plasma exchanges are the treatment of choice in severe thrombotic thrombocytopaenic purpura, their efficacy in aHUS is not guaranteed... Therefore, other therapeutic procedures, in particular complement-blocking agents, may be of benefit, and considering the severity of this condition are fully justified... To this day, >50 cases of patients who received eculizumab for aHUS have been published or included in an international multicentre prospective Phase II trial... Kim et al. and Garjou et al., in two articles that appear in this issue of the Clinical Kidney Journal, describe the outcome of aHUS in two additional cases of patients who received eculizumab for this syndrome occurring in their native kidneys... It comes as no surprise that plasma exchanges were not beneficial in the patient with MCP mutation... MCP is classically associated with a childhood onset, a spontaneous abortion of the TMA and recurrent episodes... After failure of plasma exchanges, eculizumab induced an increase in platelet counts and haemolysis was stopped... The patient with MCP mutation who was treated later than 3 months after the onset did not recover his kidney function... In these cases, the tolerability was good... It appears that eculizumab, the first targeted terminal complement inhibitor, is able to provide an effective and generally well-tolerated treatment for patients suffering from aHUS.